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Plasma Osteoprotegerin Is Associated with Mortality in Hemodialysis Patients

Marion Morena^*,, Nathalie Terrier^*, Isabelle Jaussent, Hélène Leray-Moragues, Lotfi Chalabi^||, Jean-Pierre Rivory^¶, François Maurice^¶, Cécile Delcourt^#, Jean-Paul Cristol^*, Bernard Canaud^, and Anne-Marie Dupuy^*

^* Biochemistry Laboratory; Department of Nephrology, Lapeyronie University Hospital, Montpellier; Renal Research and Training Institute, Montpellier; French National Institute of Health and Medical Research, Inserm E 0361, Montpellier; ^|| AIDER, Montpellier; ^¶ Centre Hemodialyse Languedoc Mediterranee, Montpellier; and ^# French National Institute of Health and Medical Research, Inserm U593, Université Victor Segalen Bordeaux 2, Bordeaux, France

Address correspondence to: Dr. Jean-Paul Cristol, Biochemistry Laboratory, Lapeyronie University Hospital, 371 Avenue du Doyen Gaston Giraud, 34295 Montpellier cedex 5, France. Phone: 33-467-338-314; Fax: 33-467-338-393; jp-cristol{at}chu-montpellier.fr

Received for publication March 9, 2005. Accepted for publication September 28, 2005.

	Abstract

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Expression of bone proteins resulting from transdifferentiation of vascular smooth muscle cells into osteoblasts suggests that vascular calcifications are a bioactive process. Regulating molecules such as osteoprotegerin (OPG) and receptor activator of NF-B ligand (RANKL) could play a key role in bone-vascular calcification imbalance. This study investigated the contribution of these proteins as well as mineral metabolism disorders in hemodialysis (HD) patient outcome. A total of 185 HD patients were followed up prospectively for 2 yr. In addition to clinical characteristics, mineral metabolism markers as well as OPG and soluble RANKL (sRANKL) were measured at baseline. After 2 yr, survival rates were described with Kaplan-Meier and compared with Cox regression analyses; 50 patients died (27 from cardiovascular diseases). Calcium, phosphate, and calcium x phosphate product were not associated with mortality. Both hyperparathyroidism (parathyroid hormone 300 pg/ml) and hypoparathyroidism (parathyroid hormone <150 pg/ml) were poorly associated with all-cause and cardiovascular mortality. By contrast, elevated OPG levels predicted all-cause (relative risk [RR] 2.67; 95% confidence interval [CI] 1.32 to 5.41; P = 0.006) and cardiovascular mortality (RR 3.15; 95% CI 1.14 to 8.69; P = 0.03). Low levels of sRANKL were associated with a protective effect for all-cause mortality (RR 0.45; 95% CI 0.21 to 0.94; P = 0.03). The association of OPG with all-cause mortality was stronger in patients with C-reactive protein 12.52 mg/L. In this condition, both highest (RR 5.68; 95% CI 1.48 to 22.73; P = 0.01) and lowest tertiles (RR 5.37; 95% CI 147 to 1968; P = 0.01) significantly predicted poor outcome. These results show that regulating-bone molecules, especially OPG, are strong predictors of mortality in HD patients, suggesting that OPG is a vascular risk factor, in particular in patients who have high C-reactive protein levels. OPG determination therefore should be added to the biologic follow-up of these patients.

	Introduction

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Despite technical and pharmacologic improvements achieved over the past years in the management of patients with ESRD, long-term prognosis of hemodialysis (HD) patients is still poor (1). Cardiovascular disease is the leading cause of both morbidity and mortality in HD patients (2–4), suggesting that a proper management of specific cardiovascular risk factors is required for improving clinical outcome.

Vascular calcifications now are recognized as a strong predictor of all-cause and cardiovascular mortality in this population (5). In this context, hyperphosphatemia, increased calcium x phosphate product (Ca x PO₄) and secondary hyperparathyroidism were initially considered to be of central pathophysiologic relevance (6,7) because of passive deposition in mineralized hydroxyapatite when supersaturation concentrations of calcium and phosphorus were reached in the serum. Under pathologic conditions, the expression of bone matrix proteins by vascular smooth muscle cells (VSMC) recently identified in the arteries has suggested that vascular calcification is an active, cell-mediated process secondary to VSMC transdifferentiation into osteoblast-like cells (8,9). The precise mechanisms that drive vascular calcification and its clinical consequences are still unclear. However, new insights on the vascular calcification process are emerging on a recently discovered group of regulating molecules that belong to the TNF receptor superfamily, including osteoprotegerin (OPG) and receptor activator of NF-B ligand (RANKL) (10). Indeed, OPG and RANKL, a key agonist/antagonist cytokine system, regulate important aspects of osteoclast/osteoblast formation (11,12). RANKL increases the pool of active osteoclasts by activating its specific receptor RANK located partly on osteoclastic cells, thus increasing bone resorption, whereas OPG, which neutralizes RANKL, has opposite effects. RANKL and OPG are produced by bone marrow–derived stromal cells and osteoblasts and are regulated by various calciotropic cytokines, hormones, and drugs. It is interesting that it was shown recently in general population that increased levels of OPG (13,14) and low levels of RANKL (15) were associated with an increased rate of cardiovascular mortality, probably as a result of vascular calcifications. Therefore, we prospectively assessed the associations of all-cause and cardiovascular mortality with parameters involved in vascular calcifications (divalent ion abnormalities and bioactive process including OPG and RANKL) in a cohort of HD patients who were followed up for 2 yr.

	Materials and Methods

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Study Design
A total of 185 stable HD patients who originated from one of the three dialysis facilities of Montpellier, France (an hospital-based facility [Lapeyronie University Hospital], a public nonprofit association [Aide pour l’Installation à Domicile de l’Epuration extra Rénale], and a private dialysis clinic [Centre d’Hamodialyse Languedoc Méditerranéen]) were evaluated for inclusion from October to November 2001. Informed consent was obtained from all participants. We excluded patients with symptoms or signs of acute inflammatory or infectious diseases. The included patients then were followed up prospectively yearly until January 1, 2004.

Patients and Baseline Data
The patients received either high-flux polysulfone HD or on-line hemodiafiltration treatments with ultrapure bicarbonate-buffered dialysate three times a week (mean duration 11.5 ± 1.5 h/wk) with a dialysate calcium concentration of 1.50 mmol/L (in 41.4% of patients) or 1.75 mmol/L (in 58.6% of patients). Dialysis efficiency was estimated using single pool Kt/V ratio (16).

Medical charts were reviewed for age, gender, weight, height, underlying renal disease, dialysis vintage, history of transplantation, diabetes, comorbid conditions, past or current smoking, current medication, and current hypertension. Concerning treatment of mineral metabolism disorders, 132 patients were receiving calcium carbonate, 14 were receiving sevelamer, and 77 were receiving 1 hydroxy vitamin D3.

Existence of hypertension was defined by predialysis brachial BP 140/90 mmHg and/or by a current antihypertensive treatment. Pulse pressure, as an index of aortic stiffness, was defined by the difference between systolic and diastolic BP (17). A clinical examination was carried out. Presence of atherosclerotic cardiovascular disease was defined by the presence of at least one of the three following manifestations: Coronary artery disease, cerebrovascular disease, or peripheral atherosclerotic disease.

Coronary artery disease was defined as documented angina pectoris or history of myocardial infarction. Angina pectoris was described as chest pain arising at exertion and disappearing with nitroglycerine or rest. The diagnosis may also have been done by a positive evaluation in nuclear medicine or a coronary stenosis >75% of luminal diameter. Myocardial infarction was defined as clinical symptoms, such as chest pain or dyspnea, associated with a positive electrocardiogram and elevated cardiac markers (cardiac enzymes or troponins). Cerebrovascular disease was defined as previous clinical cerebral disease (transient ischemic attack or stroke) or the presence of atheromatous plaques on internal carotid arteries. Peripheral vascular disease included clinical symptoms such as intermittent claudication, abolished peripheral pulses or diminished arterial pulses or signs of atheromatous involvement of the lower limb.

Follow-Up Period and End Point
Patients were followed yearly during 2 yr. No major modifications were made in dialysis treatment and schedules during this follow-up period. On January 1, 2003, and January 1, 2004, all patients were re-evaluated by the physicians in the dialysis centers. The dates of death, transplantation, or transfer to another dialysis center were documented. The causes of death were classified as cardiac events (myocardial infarction, congestive heart failure, and sudden death) or noncardiovascular events (infection, neoplasm, other, and unknown causes).

Laboratory Measurements
Blood samples were collected at baseline at a single midweek dialysis session (as part of our routine patient follow-up and quality insurance process) and centrifuged, and plasma samples were finally stored at –80°C for processing C-reactive protein (CRP), Ca, PO₄, intact [1-84] parathyroid hormone (PTH), bone-type alkaline phosphatase (bALP), OPG and soluble RANKL (sRANKL), and albumin.

Ca and PO₄ were assessed by colorimetric method (Olympus Apparatus, Rungis, France). CRP and albumin were determined by immunoturbidimetry method (Olympus Apparatus). Ca was adjusted for albumin levels according to the following formula: corrected calcium (mmoL/L) = measured calcium (mmol/L) + (40 – albumin [g/L]) x 0.025. PTH was measured by immunoradiometric assay (N-Tact PTH SP IRMA Kit; DiaSorin, Stillwater, MN). bALP was measured by immunochemiluminescence technique (Access Beckman Coulter, Villepinte, France). OPG (interassay CV = 6.5% [472.8 pg/ml] and 8.6% [1430.4 pg/ml]; intra-assay CV = 4.8% [477.0 pg/ml] and 3.7% [7074.0 pg/ml]) was performed by ELISA (Biovendor Laboratory Medicine, Brno, Czech Republic; normal range previously obtained in the laboratory 300 ± 102 pg/ml [18,19]). To evaluate the long-term variability of this bone marker, we repeated determination at 1 yr on 133 HD patients. Clear correlation was obtained between the two measures (OPG[+1 yr] = 0.95*OPG + 250.95; r = 0.81; P < 0.0001). In addition, the scatter of differences between the two determinations was described according to the Bland-Altman approach. More than 95% of the differences between the two levels were within the 2 SD limit. sRANKL (interassay CV = 3.9% and 7.3% [2.67 pmol/L and 3.04 pmol/L, respectively]; intra-assay CV = 5% and 3% [1.00 pmol/L and 3.20 pmol/L, respectively]) was performed by ELISA (Biomedica, Wien, Austria; normal range previously obtained in the laboratory 0.80 ± 0.40 pmol/L [19]).

Statistical Analyses
Data were expressed as mean ± SEM for normally distributed variables and as median (minimum to maximum) for nonnormally distributed variables. The Kaplan-Meier method was used to describe survival curves. Cox proportional hazards regression analysis was used to examine the associations of baseline variables with all-cause and cardiovascular mortality. Adjustments for age, gender, and dialysis vintage were initially performed to calculate adjusted relative risks (RR). Fully adjusted RR were calculated further after adjustment for age, gender, dialysis vintage, diabetes, hypertension, and smoking. Results were reported as RR with the respective 95% confidence interval (CI). P = 0.05 was considered to be significant. All analyses were carried out with SAS software, version 9.1 (SAS Institute, Cary, NC).

PTH levels and Ca/PO₄ parameters were analyzed according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) recommendations for ESRD (20). The recommended normal range was chosen as the reference value for statistical analysis. Because no consensus was reported about normal value of CRP, OPG, and sRANKL in HD patients, these variables were divided into tertile values.

We tested the potential interactions between CRP and markers of mineral metabolism (OPG, sRANKL, and PTH), by comparing separately for each marker the likelihood of the complete model (including the terms for CRP, mineral marker, and their interaction) to the likelihood of the simple model (including only the terms for CRP and the mineral marker), using the likelihood ratio.

	Results

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Baseline Characteristics of Patients
Clinical characteristics of the 185 HD patients are summarized in Table 1. Diabetes and hypertension were found in 21.6 and 22.7%, respectively. Pulse pressure median was 56 mmHg (24 to 112). Evidence of cardiovascular disease was present in 31.3% for coronary heart disease, 44.8% for cerebrovascular disease, and 43.8% for peripheral atherosclerotic disease.

All-Cause Mortality
After a 2-yr follow-up, 50 patients (23 men and 27 women) had died from cardiovascular causes (n = 27), infectious diseases (n = 10), malignancies (n = 4), severe malnutrition (n = 4), or miscellaneous causes (n = 5).

Inflammation, Mineral Metabolism, and Mortality Rate
A reported in Tables 2 and 3, high CRP level was predictive of poor outcome (RR 2.63; 95% CI 1.25 to 5.55; P = 0.01, after adjustment for age, gender, and dialysis vintage). However, its relationship with cardiovascular deaths did not reach significance. In addition, no significant association between pulse pressure and all-cause or cardiovascular deaths was observed. Regarding mineral metabolism markers, Ca, PO₄, Ca x PO₄, and bALP were not independent predictors of mortality at 2 yr, whatever the cause of mortality or the statistical adjustment for potential confounders.

OPG and sRANKL as Predictors of Mortality
As the median tertile of OPG (1550.4 to 2438.4 pg/ml) was associated with the lowest mortality rate, it was taken as the reference tertile (Tables 2 and 3). It is interesting that elevated levels of OPG predicted all-cause (RR 2.67; 95% CI 1.32 to 5.41; P = 0.01, after adjustment for age, gender, and dialysis vintage) and cardiovascular mortality rates (RR 3.15; 95% CI 1.14 to 8.69; P = 0.03 after adjustment for age, gender, and dialysis vintage). The lowest tertile of OPG was not significantly associated with all-cause and cardiovascular mortality (RR 1.42 [95% CI 0.59 to 3.40; NS] and RR 2.33 [0.72 to 7.50; NS], respectively). No correlation was observed between OPG or sRANKL and any other bone metabolism markers such as PTH levels, Ca x PO₄, PO₄ level, or bALP. Similarly, no significant correlation was observed between CRP and OPG levels (r = –0.037, P = NS) and between pulse pressure and OPG (r = 0.12, P = 0.10). Low levels of sRANKL were associated with a protective effect for all-cause mortality (RR 0.45; 95% CI 0.21 to 0.94; P = 0.03, after adjustment for age, gender, and dialysis vintage), whereas its association with cardiovascular mortality did not reach statistical significance (RR 0.48; 95% CI 0.17 to 1.31; NS, after adjustment for age, gender, and dialysis vintage).

Multivariate Analysis
Table 4 describes the proportional hazards model using all of the parameters that were significantly associated with an enhanced mortality in the first model, which includes CRP, PTH, OPG, and sRANKL. In addition, classical risk factors, such as age, gender, dialysis vintage, diabetes, hypertension, and smoking, were included. There was a significant interaction among CRP and OPG (P = 0.02); in Table 4, therefore, we present results separately for patients with CRP <12.52 mg/L and for patients with CRP 12.52 mg/L. In patients with CRP <12.52 mg/L, classical risk factors, such as age, gender, dialysis vintage, or diabetes, were the strongest risk factors for mortality. In this group, OPG and PTH were not significantly associated with mortality, whereas low sRANKL values were associated with decreased mortality (RR 0.27, P = 0.03). By contrast, in patients with CRP 12.52 mg/L, among traditional risk factors, only hypertension was significantly associated with mortality. OPG was strongly associated with mortality, with both low levels and high levels showing increased risk for mortality (RR 5.37 [P = 0.01] and RR 5.68 [P = 0.01], respectively). PTH and sRANKL were not significantly associated with mortality in this multivariate model.

View this table: [in this window] [in a new window]   Table 4. Final multivariate Cox proportional hazards analysis of factors that predict all-cause mortality among HD patients (n = 24 for CRP <12.52 mg/L and n = 26 for CRP 12.52 mg/L)

	Discussion

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Vascular calcification long has been regarded as a passive process in which disturbances in calcium phosphorus metabolism played a central role. However, expression of bone matrix proteins by VSMC in arteries recently suggested that vascular calcification was not simply passive but rather an active, cell-mediated process secondary to VSMC transdifferentiation into osteoblast-like cells (8,9). It has been shown that this transdifferentiation could be achieved in vitro by many uremic toxins (34). In addition, chondrocytes, osteoblasts, and osteoclasts have been identified in calcified atherosclerotic plaques (35,36). These cell types can express both activating proteins (osteonectin, osteocalcin, and bone morphogenic protein-2) and inhibiting proteins (osteopontin, matrix GLA-protein, and bone sialoprotein) and finally regulatory factors (Cbfa1 and OPG/RANKL) (34,37,38) of calcification. Evidence supports the assumption that the OPG/RANKL complex cytokine network may be expressed, regulated, and function in vascular physiology and pathology to regulate VSMC osteogenesis and calcification (10). Indeed, RANKL is one of the major osteoclast maturation factors, whereas OPG functions as a soluble decoy receptor for RANKL and inhibits its effects (39). Therefore, at the bone level, OPG promotes bone formation, whereas RANKL promotes bone resorption (11). In the vessel wall, several epidemiologic studies strongly suggested that elevated levels of OPG are associated with the vascular risk in the general population (13,14,40). RANKL effect is still unclear, even though preliminary results from Schoppet et al. (15) reported that low levels of RANKL were also associated with vascular risk.

In the context of HD, it is more difficult to interpret results regarding OPG and RANKL, first because OPG is not removed correctly (41), and therefore its accumulation leads to a decrease in circulating RANKL. This imbalance constitutes a major vascular risk factor (13,15,40) and is observed in our population because OPG levels were much greater and sRANKL was lower than those reported in the normal population (19). In the age-, gender-, and dialysis vintage–adjusted analysis, only the highest tertile of OPG was significantly associated with increased mortality rate, suggesting that levels >2400 pg/ml should be interpreted as a risk factor. The multivariate analysis demonstrates for the first time that OPG is an independent variable associated with mortality rate, highlighting previous observation on extent (42,43) and progression (44) of vascular calcifications. Moreover, this multivariate analysis suggests an interaction between CRP and OPG, although no direct correlation was observed between these parameters. In fact, OPG seems to be a predictor of poor outcome only in the presence of inflammation (Table 4). In this condition, as previously observed for mineral metabolism markers particularly for PTH, association of OPG with all-cause mortality tended to describe a U-shaped curve. This relationship could be dependent in part on the bone turnover rate, because preliminary works suggest that PTH levels determine OPG/RANKL in bone tissue and serum (42,44). In addition, a symmetric opposite curve was observed with sRANKL. Such observation is in agreement with the general concept that OPG and RANKL are agonist/antagonist molecules that lead to opposite effects in both bone and vascular biology. From this clinical study, it is difficult to speculate on the molecular mechanisms involved in the vasculature, especially in the presence of inflammation. Because it has been shown that OPG knockout mice develop severe and diffuse arterial calcifications (45), it could be postulated that OPG partly exerts a protective role against vascular Ca deposition. The high mortality rate observed with the lowest tertile of OPG in the presence of an inflammatory reaction could in part reflect this hypothesis (RR 5.37; 95% CI 1.47 to 19.68; Table 4). The recent finding that uremic serum enhances the expression of calcification inhibitors such as OPG and matrix GLA protein in bovine VSMC further supports an intravascular regulatory mechanism (46). However, the clear link observed with high OPG and mortality rate in age-, gender-, and dialysis vintage–adjusted analysis (Tables 2 and 3) is enhanced further in the presence of inflammation (RR 5.68; 95% CI 1.42 to 22.73; Table 4). These data suggest that the putative OPG-related compensatory mechanism could be overwhelmed in the presence of inflammation. Because in our study OPG and CRP are not directly correlated, it could be hypothesized further that OPG and CRP act through different mechanisms in HD-linked arteriopathy. Indeed, OPG, which is known as a marker of the complex process that leads to the osteoblastic transdifferentiation associated with bone matrix formation, could participate in the vascular cytokine network (13) and modulate local inflammation in the arterial wall (14). In addition, systemic inflammation could be involved further in Ca deposition on this bone-like tissue. The hepatic synthesis of circulating Ca-binding protein fetuin A, which inhibits tissue calcification, has been shown to be downregulated with inflammation (47).

Finally, in this study, multivariate adjustment for a number of potential confounders, including age and diabetes, did not materially affect the associations of OPG with mortality, whereas these two classical risk factors have been reported to influence OPG levels. This result is in agreement with our recent report showing that, in diabetes, OPG is influenced by coronary vascular disease (18).

In conclusion, this study clearly shows that among mineral metabolism markers, including PO₄, Ca x PO₄, PTH, and combination indices, OPG levels are the strongest predictors of all-cause mortality in HD patients, in particular in patients who have high CRP levels. We therefore strongly suggest the annual determination of this marker as part of the biologic follow-up of these patients in addition to inflammatory parameters.

	Acknowledgments

 
We acknowledge the nephrologists J.L. Flavier, J.Y. Bosc, M. Galy, C. Formet, F. Gérard, C. Rouanet, and I. Selcer for collaboration. The bALP reagents used in this study were generously provided by Beckman-Coulter France.

	Footnotes

 
Published online ahead of print. Publication date available at www.jasn.org.

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